INDUCTION OF HEART HEME OXYGENASE-1 (HSP32) BY HYPERTHERMIA - POSSIBLE ROLE IN STRESS-MEDIATED ELEVATION OF CYCLIC 3' 5'-GUANOSINE MONOPHOSPHATE/

Presently we have investigated the carbon monoxide generating capacity of the cardiovascular system under normal and stress conditions by ex amining the microsomal heme oxygenase system at the transcript, protei n and activity levels; and have assessed response of heart nitric oxid e (NO) synthase activity and cyclic GMP levels to stress. Heme oxygena se (HO) isozymes, HO-1 (HSP32) and HO-2, catalyze the rate limiting st ep in the only known pathway in eukaryotes for the generation of the p otential cellular message, carbon monoxide, and the antioxidant, bilir ubin. We show expression of HO-1 and HO-2 at both the transcription an d protein levels under normal conditions in the heart and descending a orta, and demonstrate the sensitivity of only the HO-1 isozyme to heat stress in these tissues. The ratio of the two HO-2 homologous transcr ipts (similar to 1.9 and 1.3 Kb) present in the atrium, ventricles and descending aorta and their levels were not altered by hyperthermia (4 2 degrees C, 20 min) when measured 1 or 6 hr after treatment. In contr ast, hyperthermia caused a rapid, robust and coordinate increase of ap proximately 10- to 32-fold in the similar to 1.8-Kb HO-1 mRNA in these tissues when measured 1-hr post-treatment. Hyperthermia also caused a significant increase in both HO-1 protein and heme degradation capaci ty in the heart. Furthermore, the induction of HO-1 protein in the hea rt was accompanied by a significant elevation in tissue cyclic GMP lev el first detected 1-hr post-treatment and was sustained 6 hr after hea t shock. However, the low level of NO synthase activity that could be detected in the heart was not significantly altered by heat shock. By using immunohistochemistry, HO-1 expression was demonstrated in the at rioventricular bundle (bundle of His) in the heart of thermally stress ed rats, and HO-2 was visualized in the endothelial lining and smooth muscle of the descending aorta. Collectively, these observations sugge st that, under normal conditions, in addition to NO produced by NO syn thase, carbon monoxide generated by both heme oxygenase isozymes in th e cardiovascular system may contribute to the regulation of tissue cyc lic GMP level. It is further suggested that under stress conditions th e HO-1 form may contribute to increased demand for messenger productio n.